Co-processed carbohydrate system as a quick-dissolve matrix for solid dosage forms

ABSTRACT

The present invention comprises a co-processed carbohydrate system, and formulations produced therefrom, which formulations are directly compressible into solid dosage forms, some of which rapidly and completely dissolve or disintegrate in the oral cavity within 60 seconds. The invention also comprises the solid dosage forms produced by directly compressing the co-processed carbohydrate system, some of which, when placed in the oral cavity, shall dissolve or disintegrate, preferably within about 60 seconds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/038,924, filed Sep. 27, 2013, which is a continuation of U.S.application Ser. No. 11/448,523, filed Jun. 6, 2006 (now U.S. Pat. No.8,545,889), which is a continuation of U.S. application Ser. No.10/274,227, filed Oct. 18, 2002 (now U.S. Pat. No. 7,118,765), whichclaims priority to U.S. Provisional Application No. 60/341,366, filedDec. 17, 2001, all of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to co-processed carbohydrate systems thatproduce formulations that are directly compressible into solid dosageforms, some of which rapidly and completely dissolve and/or disintegratein the oral cavity, preferably within about 60 seconds. The inventionalso relates to solid dosage forms produced by directly compressing aco-processed carbohydrate system, along with other ingredients, some ofwhich when placed in the oral cavity, dissolves or disintegrates,preferably within about 60 seconds.

The present invention also relates to co-processed carbohydrates thatproduce formulations that are directly compressible into solid dosageforms, which formulations, when co-processed, form particles having anon-filamentous microstructure.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 6,221,392 which was issued on Apr. 24, 2001 and U.S. Pat.No. 6,024,981 which was issued on Feb. 15, 2000 both to Khankari et al.,describe a hard tablet that is said to dissolve rapidly in the mouth ofthe patient with a minimum of grit. The tablet is created from an activeingredient mixed into a matrix of a nondirect compression filler and arelatively high lubricant level.

U.S. Pat. No. 5,576,014 which was issued on Nov. 19, 1996 to Mizumoto etal., describes intrabuccally dissolving compressed moldings including asaccharide having low moldability having been granulated with asaccharide having high moldability. The moldings are said to show quickdisintegration and dissolution in the buccal cavity and have an adequatehardness.

U.S. Pat. No. 5,720,974 which was issued on Feb. 24, 1998 to Mikano etal., describes a method of producing a fast dissolving tablet includingcompression-molding a composition having an active ingredient, acarbohydrate and a barely sufficient amount of water to moisten thesurface of particles of the carbohydrate into a tablet form and a fastdissolving tablet obtainable by the method. The active ingredient may,for example, be a vitamin, a gastrointestinal function conditioningagent or an anti-pyretic-analgesic-anti-inflammatory agent. Thecarbohydrate includes, but is not limited to sugar, starch, lactose,honey, sugar alcohols and tetroses. The amount of water to be added isabout 0.3% to 10% by weight. The fast dissolving tablet is said to havea porous structure with excellent disintegratability and solubility aswell as adequate strength.

U.S. Pat. No. 5,958,471, which was issued on Sep. 28, 1999 to Schwarz,et al., describes a spray-dried composition including two or morepolyols, such as sorbitol, mannitol, and xylitol, where mannitol ispresent in a quantity less than 10 percent by weight.

U.S. Pat. No. 6,165,511, which was issued on Dec. 26, 2000 to Schwarz,et al., describes a process for preparing a spray-dried compositionincluding a polyol. The process includes preparing an aqueous solutionof more than 80% of one or more non-hygroscopic polyols and spraying theresulting mixture into an air stream. The resulting composition of thespray-drying process contains a filamentous structure.

International Publication No. WO00/57857 (PCT/KR00/00242), publishedOct. 5, 2000, to Yuhan Corporation discloses a rapidly disintegrabletablet which includes an active ingredient, spray-dried mannitol,crospovidone, and at least one pharmaceutically acceptable excipient.Other additives, such as a lubricant and a sweetening agent may also beincluded in the tablet composition.

All patents referenced in this application are herein incorporated byreference in their entirety.

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method forproducing a directly compressible composition having a nonfilamentousmicrostructure, preferably that quickly dissolves in the buccal cavityin less than 60 seconds. The present invention also relates to a methodfor producing a quick-dissolving composition. Compositions prepared fromthe methods taught herein are also described. Finally, tablets preparedfrom the compositions are disclosed.

In one embodiment the present invention includes a method for producinga directly compressible and highly compactible composition.

In one embodiment of the method of the invention, the method includesdissolving mannitol powder and sorbitol powder into a solution, dryingthe solution in an air stream, and forming a composition that completelydissolves in the oral cavity within about 60 seconds.

In one embodiment of the method of the invention, the method includesdissolving mannitol powder and sorbitol powder into a solution, dryingthe solution in an air stream, and forming a particle having anonfilamentous microstructure from the solution.

In another embodiment of the method of the present invention, the methodincludes dissolving mannitol powder and sorbitol powder into a solution,drying the solution in an air stream, forming a particle having anonfilamentous microstructure from the solution, and forming acomposition that completely dissolves in the oral cavity, preferablywithin about 60 seconds.

In an embodiment of the method of the present invention, the methodproduces a composition having a moisture content of less than about 8%.Preferably, the moisture content is less than about 5%, and morepreferably, less than about 2%.

In another embodiment of the method of the present invention, the methodincludes adding a disintegrant to the composition. In one embodiment,the disintegrant is selected from crospovidone, croscarmellose, sodiumstarch glycolate, or combinations thereof.

In one embodiment of the method of the present invention, the methodalso includes adding a glidant to the composition. In one embodiment,the glidant is selected from colloidal silica, silica gel, precipitatedsilica, or combinations thereof.

In one embodiment of the method of the present invention, an activeingredient is added to the composition. The active ingredient is coatedor uncoated.

In another embodiment of the method of the present invention, the rangeof mannitol present in the solution is from about 60% to about 99.5%,preferably about 70% to 95%, and more preferably about 80% to 90%. Therange of sorbitol present in the solution is from about 0.5% to 40%,preferably about 5% to 30%, and more preferably about 10% to 20%.

In another embodiment of the method of the present invention, the methodincludes dry feeding a blend of dry mannitol powder and sorbitol powderinto the spray-drying chamber.

In another embodiment of the method of the present invention, the methodincludes diluting the resulting composition with a dry mixture ofmannitol and a disintegrant. In one embodiment, the disintegrant isselected from croscarmellose, crospovidone, or sodium starch glycolate,or mixtures thereof. In another embodiment, the dry mixture includesabout 90% mannitol and about 10% disintegrant.

In another embodiment of the method of the present invention, the methodincludes forming a tablet from the resulting composition.

In another embodiment of the present invention, a quick-dissolvingcomposition having at least co-spray-dried mannitol and sorbitol and adisintegrant is also described. In an embodiment, the mannitol ispresent in a range of from about 60 to about 99.5 percent and saidsorbitol is present in a range of from about 0.5 to about 40 percent ofthe co-spray dried material. In another embodiment, the range ofmannitol is about 70% to 95% and the range of sorbitol is about 5% to30%. In another embodiment, the range of mannitol is about 80% to 90%and the range of sorbitol is about 10% to 20%. The quick-dissolvingcomposition can be directly compressible.

In another embodiment of the composition of the present invention, thecomposition further includes a glidant. In one embodiment, the glidantis selected from colloidal silica, silica gel, precipitated silica, orcombinations thereof.

In another embodiment, the composition further includes at least oneactive ingredient. In one embodiment, the active ingredient is coated.In another embodiment, the active ingredient is not coated. In anotherembodiment, the composition includes coated and uncoated activeingredients.

In one embodiment of the present invention, the composition furtherincludes one or more disintegrating agents. The disintegrating agentincludes crospovidone, croscarmellose, sodium starch glycolate, orcombinations thereof.

In another embodiment of the present invention, the composition ishighly compactible and includes particles having a nonfilamentousmicrostructure including co-spray dried mannitol and sorbitol. In oneembodiment, the mannitol is present in a range of from about 60 to about99.5 percent and said sorbitol is present in a range of from about 0.5to about 40 percent of the co-spray dried material. In anotherembodiment, the range of mannitol is about 70% to 95% and the range ofsorbitol is about 5% to 30%. In another embodiment, the range ofmannitol is about 80% to 90% and the range of sorbitol is about 10% to20%. The quick-dissolving composition can be directly compressible.

The invention also encompasses tablets comprising any of thecompositions of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings. For the purpose of illustrating the invention,there are shown in the drawings preferred embodiment(s). It should beunderstood, however, that the invention is not limited to the precisearrangements and instrumentalities shown. In the drawings:

FIG. 1 is a graph depicting tablet hardness versus compaction force foreach of Formulation A (triangle), Formulation B (square), Formulation C(“x”), and Formulation D (circle).

FIG. 2 is a graph depicting friability values versus tablet hardness foreach of Formulation A (triangle), Formulation B (square), Formulation C(“x”), and Formulation D (circle).

FIG. 3 is a graph depicting disintegration times versus tablet hardnessfor each of Formulation A (triangle), Formulation B (square),Formulation C (“x”), and Formulation D (circle). The large asterisk atabout 1.5 KP represents an over-the-counter quick dissolve product.

FIG. 4A is a scanning electron micrograph (SEM) of Formulation A afterit is dried in the spray dryer (magnification 1000×).

FIG. 4B is a 2000× magnification of the SEM in FIG. 4A.

FIGS. 5A-5H include a set of scanning electron micrographs (SEMs) ofdifferent commercially available mannitol compositions after they aredried in the spray dryer.

FIG. 5A represents an SEM (magnification 100×) of spray-dried mannitolproduced by SPI Pharma, Inc. (New Castle, Del.). The moisture wasmeasured to be 1.0% KF (as measured by Karl Fischer (KF) AF8).

FIG. 5B represents FIG. 5A at 1000× magnification.

FIG. 5C represents an SEM (magnification 100×) of mannitol produced byCerestar (France). The moisture was 0.96% KF

FIG. 5D represents FIG. 5C at 1000× magnification.

FIG. 5E represents an SEM (magnification 100×) of mannitol produced byGETEC (Brazil). The moisture was 0.82% KF

FIG. 5F represents FIG. 5E at 1000× magnification.

FIG. 5G represents mannitol produced by SPI Pharma, Inc., as in FIG. 5A(magnification 100×); however, the mannitol in FIG. 5G is seeded withdry mannitol particles during the drying process. The moisture was 0.33%KF.

FIG. 5H represents FIG. 5G at 1000× magnification.

FIG. 6 is a flow diagram depicting a process for co-sprayed fluid-bedspray drying.

FIG. 7 is a graph illustrating the compactibility of a placeboformulation of co-spray dried mannitol:sorbitol mixtures seeded with dryblends of mannitol:sorbitol in the same ratio at varying feed rates.Data is represented as follows: co-spray dried mannitol:sorbitol placebohaving a feed rate of 12.5 kg/hr (circle); co-spray driedmannitol:sorbitol placebo having a feed rate of 50 kg/hr (triangle);co-spray dried mannitol:sorbitol placebo having a feed rate of 75 kg/hr(“X”); dry blend of spray-dried mannitol and crystalline sorbitolplacebo (square).

FIG. 8 is a graph illustrating in-vivo disintegration times for theformulations in the description for FIG. 7. The data is representedaccording to the legend in FIG. 7.

FIGS. 9A, 9B, and 9C include a set of SEMs illustrating the morphologyof the particles produced by co-spray drying a mannitol:sorbitol mixturecombined with seeding with a dry blend of mannitol:sorbitol in the sameratio during the spray-drying process according to one aspect of thepresent invention. The dry-feed rate used to produce the particles inFIGS. 9A-9C was 12.5 kg/hr. FIG. 9A represents the particle morphologyat 100× magnification; FIG. 9B represents the particle morphology at1000× magnification; FIG. 9C represents the particle morphology at2000×. No filamentous structure on the particles is observed.

FIGS. 10A, 10B, and 10C include a set of SEMs illustrating themorphology of the particles produced by co-spray drying amannitol:sorbitol mixture combined with seeding with a dry blend ofmannitol:sorbitol in the same ratio during the spray-drying processaccording to one aspect of the present invention. The dry-feed rate usedto produce the particles in FIGS. 10A-10C was 75 kg/hr. FIG. 10Arepresents the particle morphology at 100× magnification; FIG. 10Brepresents the particle morphology at 1000× magnification; FIG. 10Crepresents the particle morphology at 2000×. No filamentous structure onthe particles is observed.

FIG. 11 is a graph depicting the in-vivo disintegration time fordifferent placebo formulations of co-spray dried mannitol:sorbitolmixtures seeded with dry blends of mannitol:sorbitol in the same ratioat varying feed rates, and optionally, followed by a dilution of theproduct with a percentage of a mixture of MANNOGEM EZ™ (SPI Polyols,Inc., New Castle, Del.) and POLYPLASDONE XL™ (ISP Technologies, Wayne,N.J.; “EZ/XL”). Data is represented as follows: co-spray driedmannitol:sorbitol placebo having a feed rate of 50 kg/hr (triangle);co-spray dried mannitol:sorbitol placebo having a feed rate of 12.5kg/hr (circle, dashed line); co-spray dried mannitol:sorbitol placebohaving a feed rate of 75 kg/hr (“X” dashed line); co-spray driedmannitol:sorbitol placebo having a feed rate of 37.5 kg/hr and dilutedwith 20% EZ/XL (asterisk, solid line); co-spray dried mannitol:sorbitolplacebo having a feed rate of 37.5 kg/hr and diluted with 40% EZ/XL(circle, solid line); and dry blend of spray-dried mannitol andcrystalline sorbitol placebo (square).

FIG. 12 is a graph depicting compactibility for different placeboformulations as described in FIG. 11. The legend for the graph is thesame as the legend described in FIG. 11.

FIG. 13 is a graph depicting friability for different placeboformulations as described in FIG. 11. The legend for the graph is thesame as the legend described in FIG. 11.

Both the foregoing general description and the following detaileddescription are exemplary and explanatory and are intended to providefurther explanation of the invention as claimed. Other objects,advantages, and novel features will be readily apparent to those skilledin the art from the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes quick dissolving solid dosage formsproduced from quick dissolving formulations including a co-processedcarbohydrate system. In one embodiment, the solid dosage forms of thepresent invention are prepared by direct compression. The solid dosageforms rapidly dissolve or disperse in the oral cavity of a patient, thusreleasing any active ingredient contained within the formulation.

The present invention also includes a co-processed carbohydrate system,and formulations produced therefrom that are directly compressible intosolid dosage forms which rapidly and completely dissolve and/ordisintegrate in the oral cavity, preferably within about 60 seconds.

The present invention also includes co-processed carbohydrates, andformulations produced therefrom, which co-processed carbohydrates andformulations comprise particles having a non-filamentous microstructure.The co-processed carbohydrates and the formulations produced thereforeare directly compressible into solid dosage forms.

The present invention is described herein using several definitions, asset forth below and throughout the application.

Definitions

The term “about” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which it is used. Ifthere are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” shallmean up to plus or minus 10% of the particular value.

The phrase “completely dissolve or disintegrate” used in the context ofthe present invention, means that the solid dosage form dissolves ordisintegrates to an extent that the patient believes the solid dosageform to be completely dissolved or disintegrated. That is, the patientcan no longer detect any significant lumps or large particles of theoriginal solid dosage form. Instead, at the point in time when the soliddosage from has completely dissolved or disintegrated in the oral cavityof the patient, the solid dosage form preferably has a creamy andpleasant mouthfeel that is conducive to swallowing.

The terms “solid dosage form,” “tablet,” and “solid preparation” areused synonymously within the context of the present invention. Theseterms should be construed to include a compacted or compressed powdercomposition obtained by compressing or otherwise forming the compositionto form a solid having a defined shape.

The term “directly compressible” means that the composition can becompressed to tablet form on standard tableting machines (including, butnon limited to high speed tableting machines) using standard (i.e.,without any specially machined, shaped or coated surfaces) punches anddies, without any significant amount of the composition adhering to thepunches and dies.

The term “oral cavity” should be construed to include, but should not belimited to the buccal cavity.

The term “co-processed carbohydrate” means the processing of at leasttwo polyols together to make a single product. For example, mannitol andsorbitol may be co-spray dried by first preparing a single solution ofmannitol and sorbitol. Another example includes the co-granulation ofmannitol and sorbitol.

The term “co-processed carbohydrate system” shall be construed toinclude a co-processed carbohydrate plus a disintegrant and a glidant.

The term “co-processed carbohydrate system formulation or composition”shall be construed to include the co-processed carbohydrate system plusan active ingredient to be formed into a tablet.

It has been discovered that the existing processes, products, or systemsdirected towards rapid disintegration or dissolution in the mouth havelimitations in certain aspects. Specifically, until now it has beendifficult to produce a tablet that is robust (e.g., low friability, lowejection forces, sufficient hardness) enough to be processed in highspeed tableting machines and shipped in low cost packages, and at thesame time retain rapid disintegration or dissolution properties. This isespecially obvious when producing a tablet having high doses of activeingredients (AIs) or when producing a tablet having AIs coated withdifferent polymers, waxes, and the like for taste-masking purposes.

An advantage of the formulations of the present invention is that theycan be formed into high quality tablets on standard tableting machines(including high speed tableting machines such as those made by Killianor Korsh, capable of producing at least 75,000 tablets per hour) usingstandard punches and dies. The “standard” punches and dies referred toabove are far less expensive to produce and maintain than the coated(e.g., teflon-coated) punches and dies used to produce tablets fromformulations that are sticky or difficult to compress.

In one embodiment, the present invention overcomes these limitations byutilizing a co-processing technology that ultimately produces aformulation that is compressible into a tablet. This tablet is robustenough to withstand stress of handling during production, packaging andtransportation, without special processing or handling, while retainingrapid disintegration or dissolution properties, in the oral cavity.

In one embodiment, a co-processed carbohydrate system formulationaccording to the present invention includes, but is not limited to atleast two co-processed carbohydrates, one or more disintegrating agents,and one or more glidants. It is thought that the co-processedcarbohydrate is the ingredient of the formulation that providescompactibility of the composition and a pleasant mouthfeel to thepatient. The disintegrating agent aids in achieving maximal rapiddisintegration of the solid dosage form. Finally, the glidant functionsas an anti-caking agent and flow aid, and also aids in minimizingadherence of the individual materials of the formulation to the punchesand dies of the tableting machinery.

Co-processing of carbohydrates includes, but is not limited toco-granulating at least two granular or crystalline polyols,co-granulating at least two spray-dried polyols, or co-granulating aspray dried polyol and a granular or crystalline polyol. Co-processingalso includes, but is not limited to co-spray drying at least twopolyols.

Carbohydrates useful in the present invention include, but are notlimited to polyols, which are sugar alcohols of the general formulaCH₂OH—(CHOH)_(n)—CH₂OH, where n is 2 to 6, and preferably 3 to 6, andtheir dimeric anhydrides. Preferably, the polyols include, but are notlimited to sorbitol, mannitol, erythritol, maltitol, lactitol, isomalt,and mixtures thereof, and sugars such as lactose, fructose, dextrose,sucrose, maltose, and mixtures thereof.

In one embodiment of the present invention, a co-processed carbohydratesystem formulation is prepared using mannitol and sorbitol as thecarbohydrates as follows. First, mannitol is prepared from a 55 percenthigh fructose corn syrup, which is hydrogenated by feeding the syrupinto an autoclave in the presence of a catalyst. The liquid obtainedfrom this hydrogenation step is a mixture of about 40 percent mannitoland about 60 percent sorbitol. The mannitol is crystallized out ofliquid solution by chilling the solution, and the mannitol is collectedusing centrifugation. The precipitated mannitol is then transferred to abelt for washing and then dried to form a powder mannitol. Typically,the prepared mannitol powder contains about 98 percent mannitol and upto about 2 percent sorbitol.

The prepared mannitol powder, and a sorbitol powder are then dissolvedin hot water to form a solution, and the temperature of the solution ismaintained at about 80 to 85 degrees Celsius. The ratio of mannitol tosorbitol can vary. In one embodiment, the mannitol:sorbitol ratio rangesfrom about 99.5:0.5 to about 60:40. In one embodiment, the ratio ofmannitol to sorbitol is about 99.5:0.5. In another embodiment, the ratioof mannitol to sorbitol is about 90:10. In another embodiment, the ratioof mannitol to sorbitol is about 80:20. In another embodiment, the ratioof mannitol to sorbitol is 88:12, and in a separate embodiment the ratioof mannitol to sorbitol is 92:8. In another embodiment, the ratio ofmannitol to sorbitol is about 60:40. Preferably, the mannitol content isequal to or higher than the sorbitol content.

At this point, the polyol composition is spray-dried. Any spray dryer isuseful in the present invention. In one embodiment of the invention, an51 Spray Fluid Bed Dryer with a 2.1 meter diameter is used (DRYTEC;Tonbridge, Kent, ENGLAND). The spray dryer operates by atomizing theliquid feed material (the co-processed polyol composition) in a streamof air or other gas. The main use of the spray drying equipment isdrying but the equipment can also be used for agglomerating, congealing,encapsulation, cooling and/or conditioning the composition of thepresent invention. A flow diagram depicting the operation pattern of thefluid bed spray dryer is shown in FIG. 6.

Referring to FIG. 6, air for drying is heated by a heater 1 and entersthe top of a drying chamber 4 through a hot air duct 8. A feed pump 2delivers the liquid feed through feed line 3 to an atomizer which spraysthe composition in fine droplets into a hot air stream entering the topof a drying chamber 4. This causes rapid drying due to the large liquidarea exposed. In the present invention, one of several atomizers can beused. For example, a centrifugal driven atomizer, a two fluid nozzleusing a jet of compressed air to atomize the feed, or a pressure nozzleatomizer can be used in the present invention.

An integrated fluid bed 10 is attached at the bottom of chamber 4. Thefines and air leave from a side outlet 9 of the cone of drying chamber 4to a cyclone 5. Cyclone 5 separates the fines from the air. The air isexhausted out through a bag filter 6. The fines are recycled to the topof drying chamber 4 into a wet zone 11 where agglomeration takes place,and drop into integrated fluid bed 10. The action of the fluidization bythe hot air supplied to the fluid bed allows the coarser particles todry further and the fines are taken away to cyclone 5.

The polyol solution is then fed into the integrated spray fluid beddrying chamber unit under sealed conditions and a controlled stream ofhot air at a temperature of about 200 degrees Celsius dries the solutionin the form of fine droplets. Once the desired particle size isachieved, the polyol (mannitol/sorbitol) product is collected. Particlesize can range from about 0.1 to 500 microns. In one embodiment of thepresent invention, at least 85 percent of the particles are about 100microns or greater. In another embodiment of the present invention, atleast 50 percent of the particles are about 100 microns or greater. Thesmaller particles (“fines”) generated during this process are recycledback to the top of drying chamber 4 for further agglomeration.

The moisture content of the resulting co-processed polyol particle ispreferably less than about 8%, and even more preferably, less than about5%, and even more preferably, the moisture content is less than 2%. Inone embodiment of the present invention, the moisture content of theresulting particle is about 0.3%.

As shown in FIGS. 4A and 4B, the final co-spray dried polyol compositionhas an irregular and globular or crystalline-like structure whenexamined under scanning electron microscopy.

The final co-spray dried polyol composition may have a surface shape(i.e., smooth surface, spherical in nature, with agglomerated particles)as depicted in the SEMs in FIGS. 5A-5F.

In one embodiment of the present invention, the co-processedmannitol:sorbitol ratio may be diluted after the co-spray drying processwith a percentage of a co-granulated blend of mannitol and adisintegrant. Preferably, the co-processed mannitol:sorbitol ratio isdiluted with up to about 50% of a co-granulated blend of about 90%MANNOGEM EZ™ (SPI Pharma, Inc., New Castle, Del.) and/or about 10%POLYPLASDONE-XL™ (ISP Technologies, Wayne, N.J.). Preferably, theco-processed mannitol:sorbitol is diluted with about 20% to 40% of theco-granulated blend of MANNOGEM EZ™ and/or POLYPLASDONE-XL™. In anotherembodiment, the co-processed mannitol:sorbitol is diluted with about 20%of the co-granulated blend of MANNOGEM EZ™ and POLYPLASDONE-XL™, and inanother embodiment, the co-processed mannitol:sorbitol is diluted withabout 40% of the co-granulated blend of MANNOGEM EZ™ ANDPOLYPLASDONE-XL™.

In one preferred embodiment of the present invention, the spray-driedmannitol/sorbitol polyol composition may first be seeded with dryparticles of mannitol/sorbitol in the same proportion as the aqueoussolution prepared for co-spray drying. Referring to FIG. 6, the dryparticles are introduced into the fines recycle system of the spraydryer. In one embodiment, this is achieved using a vibratory feederwhich is positioned at the inlet to a fines recycle fan 7. The dryparticles are blended in a ribbon blender prior to loading the vibratoryfeeder. It is thought that introducing the dry particles into the finesrecycle system may be advantageous in decreasing the moisture level ofthe final product.

The introduction of dry particles and/or the decrease in moisture levellead to a difference in morphology of the resulting co-spray driedparticle. As shown in FIGS. 5G and 5H, the co-spray dried polyolcomposition that is first seeded with dry particles has a sphericalparticle shape without a filamentous structure on the surface, and has adecreased moisture content, from about 1% to about 0.3% of the particleweight. It is hypothesized that the lack of filamentous structure on thespherical particle shape may increase the flowability and enhance thequick-dissolve aspects of the co-processed carbohydrate system (compareFIG. 3 and FIG. 8).

The present invention also includes a composition which is not aquick-dissolve, may be produced by co-spray drying a polyol compositionin an air stream, whereby the polyol composition is seeded with drypolyol particles. The resulting composition includes particles having anonfilamentous microstructure.

Dry particles may be introduced at a rate of from about 1 kg/hr to about100 kg/hr. Preferably, the feed rate is about 12.5 kg/hr to about 75kg/hr, and more preferably, the feed rate is about 50 kg/hr Morepreferably, the dry feed rate is about 20 kg/hr. The feed ratesapparently do not impact the morphology of the resulting product.

By way of example and not by limitation, a mannitol/sorbitol solutionmay be prepared having a total mass of 511 kg, 230 kg of which isattributed to the mannitol and sorbitol. At a total feed rate of about75 kg/hr, about 20 kg/hr of dry particles will be introduced and about55 kg/hr of the mannitol/sorbitol solution will be introduced into thespray dryer.

In another embodiment of the present invention, the solid preparation ofthe present invention comprises:

65-92% by weight of a polyol or mixture of polyols;

2-8% by weight of a cross-linked polyvinylpyrrolidone;

2-6% by weight of sodium croscarmellose use;

3-12% by weight of starch;

0.05-0.5% by weight silica gel; and

0.05-0.5% by weight colloidal silica.

In addition to the components identified above, the preparation mayoptionally contain from 8-28% by weight of other components that aresuitable for ingestion by humans and which do not adversely affect theability of the final solid preparation to completely dissolve ordisperse within 60 seconds of being placed in the buccal cavity of theuser.

In another embodiment of the present invention, the formulationcomprises:

75-90% by weight of a polyol or mixture of polyols;

3-7% by weight of a cross-linked polyvinyl pyrrolidone;

1-4% by weight of sodium croscarmellose;

4-10% by weight of starch

0.05-0.3% by weight silica gel; and

0.05-0.3% by weight colloidal silica.

In another embodiment of the present invention, the formulationcomprises:

80-88% by weight of a polyol or mixture of polyols;

3.5-6% by weight of a cross-linked polyvinyl pyrrolidone;

2.5-3.5% by weight of sodium croscarmellose;

5-9% by weight of starch;

0.05-0.25% by weight silica gel; and

0.05-0.25% by weight of colloidal silica.

In another embodiment of the present invention, the formulationcomprises:

84-85% by weight of a polyol or mixture of polyols;

4-5% by weight of a cross-linked polyvinyl pyrrolidone;

2.9-3.2% by weight of sodium croscarmellose;

7-8% by weight of starch;

0.15-0.20% by weight silica gel; and

0.15-0.20% by weight of colloidal silica.

The polyols that are suitable for use in the formulation of the presentinvention are sorbitol, mannitol, maltitol, erythritol, xylitol andlactitol and mixtures of these polyols. In one embodiment of the presentinvention, the polyol or mixture of polyols used in the formulationincludes at least one polyol selected from the group consisting ofmannitol, maltitol and sorbitol.

In another embodiment of the present invention, the polyol component ofthe composition comprises spray-dried mannitol or a spray-dried mixtureof mannitol and sorbitol or a spray-dried mixture of mannitol andxylitol.

In another embodiment of the present invention, two or more polyols or apolyol and a sugar (e.g., maltose) are coprocessed (e.g., byspray-drying or granulation techniques) to form the polyol component.

The compositions of the present invention provide the formulator with aflexible platform that can be used to prepare a variety of solidpreparations that contain one or more active ingredients and willdissolve quickly in the buccal cavity of the user.

Many different disintegrating agents can be used to prepare theco-processed carbohydrate system. Such agents include, but are notlimited to crospovidone, sodium croscarmellose, sodium starch glycolate,and mixtures thereof. The disintegrating agent is preferably present inthe co-processed carbohydrate system in a range of from about 1 percentto about 20 percent of the total weight of the system. In one embodimentof the present invention, the disintegrating agent used to prepare theco-processed carbohydrate system is cross-linked polyvinyl pyrrolidone(crospovidone) and is present in the co-processed carbohydrate system atabout 10 percent of the total weight of the system.

The cross-linked polyvinyl pyrrolidone, sodium croscarmellose and starchact to hasten the disintegration of the solid preparation by absorbingwater.

Glidants useful in preparing the co-processed carbohydrate systeminclude, but are not limited to silica gel, colloidal silica,precipitated silica, and mixtures thereof. The glidant component of theco-processed carbohydrate system preferably is present in a range offrom about zero percent to about five percent of the total weight of thesystem. One embodiment of the present invention utilizes silica gel asthe glidant in preparing the co-processed carbohydrate system, and thesilica gel preferably is present in about 0.25 percent of the totalweight of the system.

Preferred starches for use in the compositions of the present inventioninclude pregelatinized starch, such as Starch 1500 (from Colorcon, WestPoint, Pa.) and National 1551 (National Starch & Chemical Co.,Bridgewater, N.J.).

The silica gel acts to improve the flow properties of the compositionand minimize the amount of material that sticks to the punches and diesduring tableting. The colloidal silica acts to improve the flowproperties of the composition before it is tableted.

In addition to the carbohydrate(s), disintegrating agent, and glidant(i.e., the co-processed carbohydrate system), the tablet composition mayalso comprise any of the following ingredients without affecting thequick-dissolve characteristic of the co-processed carbohydrate system:

-   -   One or more coated and/or uncoated active ingredients (AIs).    -   One or more flavors    -   One or more colors    -   One or more lubricants, including, but not limited to sodium        stearyl fumarate, glyceryl behenate, and magnesium stearate        (“flow aids”)    -   Citric acid and/or ascorbic acid    -   One or more sweetening agents including, but not limited to        sucralose, aspartame, and acesulfam-K    -   Tableting aids.

There is no limitation to the active ingredient (AI) that can be usedwith the present invention. Active ingredients include, but are notlimited to pharmaceutical ingredients and nutraceutical ingredients.Examples of pharmaceutical ingredients that can be used include, but arenot limited to gastrointestinal function conditioning agents, including,but not limited to bromopride, metoclopramide, cisapride, anddomperidone; anti-inflammatory agents, including, but not limited toaceclofenac, diclofenac, flubiprofen, sulindac, and celecoxib;analgesics, including, but not limited to acetominophen and aspirin;agents for erectile dysfunction therapy, including, but not limited tosildenafil and apomorphine; anti-migraines, including, but not limitedto sumatriptan and ergotamin; antihistaminic agents, including, but notlimited to loratadine, fexofenadine, pseudoephedrine and cetirizine;cardiovascular agents, including, but not limited to nitroglycerine andisosorbide dinitrate; diuretics, including, but not limited tofurocemide and spironolactone; anti-hypertensive agents, including, butnot limited to propranolol, amlodipine, felodipine, nifedipine,captoprile, ramiprile, atenolol, and diltiazem; anti-hypolipidemicagents, including, but not limited to simvistatin, atrovastatin, andpravastatin; anti-ulcer agents, including, but not limited tocimietidine, ranitidine, famotidine, omeprazole, and lansoprazol;anti-emetics, including, but not limited to meclizine hydrochoride,ondansetron, granisetron, ramosetron, and tropisetron; anti-asthmaticagents, including, but not limited to aminophylline, theophylline,terbuttaline, fenoterol, formoterol, and ketotifen; anti-depressants,including, but not limited to fluoxetine and sertraline; vitamins,including, but not limited to B1, B2, B6, B12 and C; anti-thromboticagents, including, but not limited to sulfinpyrazone, dipyridamole, andticlopidine; chemotherapeutic agents, including, but not limited tocefaclor, bacampicillin, sulfamethoxazole, and rifampicin; hormones,including, but not limited to dexamethasone and methyltestosterone;anti-thelmintic agents, including, but not limited to piperazine,ivermectine, and mebendazole; and anti-diabetic agents, including, butnot limited to acarbose, gliclazid, and glipizid.

Preferable pharmaceutical ingredients which may be used in the presentinvention include, but are non limited to acetaminophen, pseudoephedrinehydrochloride, dextromethorphan hydrobromide, dompereidone, famotidine,meclizine hydrochloride, scopolamine hydrobromide, ondansetron,cisapride, granisetron, sildenafil, loratadine, and amlodipine.

Examples of nutraceutical ingredients include, but are not limited toany ingredient that is thought to have a beneficial effect on humanhealth. Such ingredients include coenzyme Q-10, chondroitoin, echinacea,ephedra, glucosamine, garlic, ginkgo biloba, ginseng, grape seedextract, guarana, hawthorn, herbs, kava, kola nut, lutein, St. John'swort, vinpocetine, and yohimbe.

There is no limitation on color or flavor that is useful in the presentinvention, and these characteristics will likely be chosen based on theage of the patient consuming the solid dosage form. Those of skill inthe art will know which colors and flavors are useful in the presentinvention. Color and flavor are inert ingredients and generally do nothave any effect on the efficacy of the tablet.

In one embodiment of the present invention, the co-processedcarbohydrate formulation is directly compressed into a solid dosage form(e.g., a tablet) using a standard compression equipment (e.g., atableting press). One embodiment of the directly compressed solid dosageform of the present invention interacts with saliva in the oral cavityof a patient and completely dissolves or disintegrates in the oralcavity into an easily swallowable form, preferably within about 60seconds.

In an embodiment of the invention, the solid dosage form completelydissolves or disintegrates into an easily swallowable form within about25 to 50 seconds after placing the tablet in the oral cavity.

The tablets produced in the present invention preferably have a tablethardness in the range of about 10 newtons to about 100 newtons and afriability (standard USP test method) in the range of about 0.0 percentto about 5 percent.

In one embodiment of the present invention, the tablets produced have atablet hardness in the range of about 20 newtons to about 60 newtons anda friability (standard USP test method) in the range of about 0.0percent to about 2 percent, and would dissolve or disintegrate in theoral cavity within about 45 seconds.

Thus, preferably, the present invention makes it possible to producehigh quality, robust tablets that show rapid dissolution ordisintegration properties in a cost effective manner. The cost savingsare primarily due to the inexpensive ingredients and processes involved,as described herein.

The quick dissolving formulations of the present invention may be usedas a delivery platform for one or more active ingredients. One or moreactive ingredients may be mixed with the quick dissolving co-processedcarbohydrate system and formed into a solid preparation, such as atablet. In another embodiment, additional ingredients such as alubricant, flavor, color, or sweetening agent may also be added to theformulation and formed into a solid preparation.

When the solid preparation is placed in the oral cavity of a patient, itinteracts with saliva and rapidly dissolves or disperses in the oralcavity of the patient. As the solid preparation dissolves in the oralcavity of the patient, it releases the one or more active ingredientscontained in the solid preparation.

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all references to a publiclyavailable document, including but not limited to a U.S. patent, arespecifically incorporated by reference.

Example 1 Formulation A

A rapidly dissolving tablet in accordance with the present invention,was produced as follows. A mixture of 547.48 grams of co-processedcarbohydrate system consisting of mannitol and sorbitol in a 90:10 ratio(SPI Pharma Inc., New Castle, Del.), 61.00 grams of Polyplasdone-XL (ISPTechnologies, Wayne, N.J.) and 1.53 grams of Syloid®244 FP (W. R. Grace& Co., Columbia, Md.) were blended in a Turbula Mixer for 10 minutes.

Formulation A (600.6 grams) was then blended in an 8-quart V-blenderalong with 113.48 grams of acetaminophen microcaps, 16.64 grams ofpseudoephedrine HCl microcaps and 25.664 grams of dextromethorphan HBrmicrocaps (Eurand America Inc., Vandalia, Ohio), 16 grams of GrapeFlavor # FAEB895 (Wild Flavors, Inc., Cincinnati, Ohio), 2 grams ofsucralose (Ortho-McNeil Pharmaceuticals Raritan, N.J.), 8 grams ofanhydrous citric acid, and purple color # LB1868 (Colorcon, West Point,Pa.) for 10 minutes. Sixteen grams of sodium stearyl fumarate (PenwestPharma, Patterson, N.Y.) was added to the mixture and the mixture wasblended for 6 minutes. The blend was then discharged and tableted usingstandard tableting procedures.

Example 2 Formulation B

A rapidly dissolving tablet was produced as follows. A mixture of 547.48grams of spray-dried mannitol (about 80% of total formulation) blendedwith granular sorbitol (about 10% of total formulation), 61.00 grams ofPolyplasdone-XL (ISP Technologies, Wayne, N.J.) and 1.53 grams ofSyloid®244 FP (W. R. Grace & Co., Columbia, Md.) were dry-blended in aTurbula Mixer for 10 minutes.

Formulation B (600.6 grams) was then blended in an 8-quart V-blenderalong with 113.48 grams of acetaminophen microcaps, 16.64 grams ofpseudoephedrine HCl microcaps and 25.664 grams of dextromethorphan HBrmicrocaps (Eurand America Inc., Vandalia, Ohio), 16 grams of GrapeFlavor # FAEB895 (Wild Flavors, Inc., Cincinnati, Ohio), 2 grams ofsucralose (Ortho-McNeil Pharmaceuticals Raritan, N.J.), 8 grams ofanhydrous citric acid, and purple color # LB1868 (Colorcon, West Point,Pa.) for 10 minutes. Sixteen grams of sodium stearyl fumarate (PenwestPharma, Patterson, N.Y.) was added to the mixture and the mixture wasblended for 6 minutes. The blend was then discharged and tableted usingstandard tableting procedures.

Example 3 Formulation C

A rapidly dissolving tablet was produced as follows. A mixture of 547.48grams of spray-dried mannitol (about 80% of total formulation) blendedwith spray-dried sorbitol (about 10% of total formulation; SPI PharmaInc., New Castle, Del.), 61.00 grams of Polyplasdone-XL (ISPTechnologies, Wayne, N.J.) and 1.53 grams of Syloid®244 FP (W. R. Grace& Co., Columbia, Md.) were dry-blended in a Turbula Mixer for 10minutes.

Formulation C (600.6 grams) was then blended in an 8-quart V-blenderalong with 113.48 grams of acetaminophen microcaps, 16.64 grams ofpseudoephedrine HCl microcaps and 25.664 grams of dextromethorphan HBrmicrocaps (Eurand America Inc., Vandalia, Ohio), 16 grams of GrapeFlavor # FAEB895 (Wild Flavors, Inc., Cincinnati, Ohio), 2 grams ofsucralose (Ortho-McNeil Pharmaceuticals Raritan, N.J.), 8 grams ofanhydrous citric acid, and purple color # LB1868 (Colorcon, West Point,Pa.) for 10 minutes. Sixteen grams of sodium stearyl fumarate (PenwestPharma, Patterson, N.Y.) was added to the mixture and the mixture wasblended for 6 minutes. The blend was then discharged and tableted usingstandard tableting procedures.

Example 4 Formulation D

A rapidly dissolving tablet in accordance with the present invention,was produced as follows. A mixture of 547.48 grams of co-processedcarbohydrate system consisting of mannitol and sorbitol in an 80:20ratio (SPI Pharma Inc., New Castle, Del.), 61.00 grams ofPolyplasdone-XL (ISP Technologies, Wayne, N.J.) and 1.53 grams ofSyloid®244 FP (W. R. Grace & Co., Columbia, Md.) were blended in aTurbula Mixer for 10 minutes.

Formulation D (600.6 grams) was then blended in an 8-quart V-blenderalong with 113.48 grams of acetaminophen microcaps, 16.64 grams ofpseudoephedrine HCl microcaps and 25.664 grams of dextromethorphan HBrmicrocaps (Eurand America Inc., Vandalia, Ohio), 16 grams of GrapeFlavor # FAEB895 (Wild Flavors, Inc., Cincinnati, Ohio), 2 grams ofsucralose (Ortho-McNeil Pharmaceuticals Raritan, N.J.), 8 grams ofanhydrous citric acid, and purple color # LB1868 (Colorcon, West Point,Pa.) for 10 minutes. Sixteen grams of sodium stearyl fumarate (PenwestPharma, Patterson, N.Y.) was added to the mixture and the mixture wasblended for 6 minutes. The blend was then discharged and tableted usingstandard tableting procedures.

Table 1 represents the composition of a tablet of any of theformulations:

TABLE 1 Composition of a Tablet Ingredient mg/Tablet Formulation A, B, Cor D 900.9 Coated Acetaminophen 170.22 Coated Pseudoephedrine HCl 24.96Coated Dextromethorphan HBr 38.496 Flavor (grape) 24 Sweetener(sucralose) 3 Citric acid 12 Color (purple) 2.4 Lubricant (sodiumstearyl fumarate) 24

Compaction profiles, that is, determination of maximum tablet hardnessvalues, friability values, and disintegration time for each of theFormulations A, B, C and D were determined.

Results

Compaction Profile of the Formulations

FIG. 1 shows that a 100 percent increase in tablet hardness is attainedusing the co-spray dried carbohydrate systems (Formulations A and D)compared to simple dry-blending of the ingredients (Formulations B andC). Formulation D achieved the highest tablet hardness at 11.5 KP, andcapping was not observed.

At a compression force of 13 KN, Formulations A and D both display atleast double the tablet hardness of either Formulation B or C. At acompression force of 15 KN, Formulation B caps at a tablet hardnessvalue of 3.3, while Formulations A and D have tablet hardness values ofabout 6.2 and 7.9, respectively, almost double the tablet hardness ofFormulation B. At a compression force of 17 KN, Formulation C caps at atablet hardness of 3.85 KP, while Formulations A and D exhibit tablethardness values of about 8 and 9.9, respectively. Thus, Formulations Aand D exhibit a trend of averaging at least about double the tablethardness of Formulations B and C at any given compression force.

Therefore, the co-spray dried carbohydrate system is superior ascompared to simply dry-blended ingredients, in preparing tablets with atleast a 100 percent increase in tablet hardness over dry-blendedingredients.

TABLE 2 Maximum Hardness Values Maximum Attainable Formulation Hardness(KP) before Capping is observed Formulation A  9.2 ± 1.2 KP FormulationB  3.3 ± 0.3 KP Formulation C  3.9 ± 0.8 KP Formulation D 11.6 ± 0.5 KP(No capping observed)Friability of the Formulations

A friability value of about 1 percent or less is desirable for tabletsin order for them to withstand the stress of handling during production,packaging, and transport. Formulations A and D achieved low friabilitylevels as shown in FIG. 2, which friability remained low, and evendecreased as tablet hardness increased. For example, at a tablethardness of about 4 KP, friability of Formulations A and D were about 1percent, while friability for Formulation C was at about 7.5 percent.Formulation B, at a tablet hardness of about 2.5 KP, had a friability of5.5 percent, and was subsequently eliminated. Only Formulations A and Dhad tablet hardness of greater than 4 KP, and friability decreasedsteadily to about 0.1 percent at a tablet hardness 8 KP. At 11 KP, onlyFormulation D remained, and friability was essentially zero.

The overall trend shown in FIG. 2 is that friability essentiallydecreases as tablet hardness increases. In order for a tablet towithstand stresses associated with handling and packaging, the need fortablets with increased hardness values (and therefore decreasedfriability values as FIG. 2 indicates) is required. Only Formulations Aand D, which comprise the co-processed carbohydrate system, attainhigher tablet hardness values thereby resulting in decreased friabilityvalues.

Thus, the co-spray dried carbohydrate system achieves a much lowerfriability percent as compared with the same ingredients prepared asdry-blends.

Disintegration Times in Oral Cavity for Different Formulations

FIG. 3 shows disintegration times in the oral cavity, for theFormulations A, B, C, and D. Disintegration time ranged from about 30seconds to about 60 seconds varying with tablet hardness up to about 8KP. Over-the-counter quick-dissolve tablets provide a reference point(indicated by an arrow), having a tablet hardness of about 1.5 KP and adisintegration time of about 42 seconds.

Formulation A tablet hardness ranged from about 2.5 KP to about 9.2 KP,and in-vivo disintegration times for Formulation A ranged from about 37seconds to about 55 seconds, increasing steadily from a hardness ofabout 2.5 KP to about 8 KP. Disintegration time dropped off to about 49seconds when measured at a tablet hardness of about 9.5 KP.

Formulation B had a tablet hardness range of about 2 to about 3 KP.Disintegration times for Formulation B ranged from about 30 to about 35seconds, with no discernible relationship to tablet hardness.

Formulation C displayed a tablet hardness range of from about 3 to about4 KP. Disintegration times for Formulation C increased steadily astablet hardness increased, from about 32 seconds to about 40 seconds.

Formulation D exhibited a tablet hardness range of from about 3 KP toabout 11.5 KP. From about 3 KP to about 8 KP, disintegration timeincreased steadily from about 42 seconds to about 58 seconds. From about8 KP to about 11.5 KP, disintegration time increased more dramaticallyfrom about 58 seconds to about 90 seconds.

At a tablet hardness of about 3 KP, all of the formulations have adisintegration time of between about 30 and 45 seconds, however, theerror bars shown within each of the Formulations indicate that variancewithin this range is not substantially significant. At a tablet hardnessof about 4 KP, Formulations A, C, and D exhibited disintegration timesof between about 40 and 45 seconds, also which variance isinsignificant. Formulation B did not achieve a tablet hardness beyondabout 3.3 KP.

At a tablet hardness of about 8, Formulations A and D exhibiteddisintegration times of about 55 and 58 seconds, respectively, and thisdifference, according to the standard error, is not significant.

Overall, disintegration times do not exceed 60 seconds over any tablethardness up to about 9.2 KP. Disintegration time stayed fairly constantbetween tablet hardness values of about 4 KP and about 7 KP, andincreased only slightly, by about 5 seconds between tablet hardnessvalues of about 7 KP and 8 KP. Again, the error bars indicate that thisslight increase in disintegration time is insignificant. Thus, it can beconcluded that tablet hardness has no substantial effect on in vivodisintegration time (referring to disintegration time within the buccalcavity).

The co-spray dried carbohydrate system in Formulations A and D achievelower friability and increased tablet hardness, but do not substantiallyaffect the quick-dissolving disintegration properties of the tablet ascompared with Formulations B and C.

The data from the above experiments clearly show that the co-spray driedcarbohydrate system provides strong, high-quality tablets that arerobust enough to withstand the stress of handling and transport whileretaining rapid dissolution or disintegration properties.

Example 5 Preparation of a Mannitol:Sorbitol Co-Processed Carbohydrate

The main objective of this experiment was to compare the quality ofagglomerates produced from spray drying a mixture of mannitol andsorbitol in the proportion of about 88% Mannitol to about 12% Sorbitol,using mannitols supplied by SPI Pharma, Inc. (New Castle, Del.), GETEC(Brazil), and Cerestar (France). The sorbitol was crystalline and wasprovided by SPI Pharma, Inc. (New Castle, Del.). Another objective wasto maintain a low moisture content, preferably less than 1%.

Materials and Methods

The following materials were used to carry out the present experiment:GETEC Mannitol Batch No. 10519387 (Item No. 10133), SPI Pharma Batch No.3086E2 (MANNOGEM-EZ™ Powder Mannitol), Cerestar Batch No. GQ8641 (C*MANNIDEX™ 16700), and Sorbitol Batch No. 4071C2 (SORBOGEM™, SPI Pharma,Inc). A S1 Spray Fluid Bed Dryer, capable of operating at up to 450° C.inlet temperature was used to conduct the experiment.

The mannitol:sorbitol composition (“feed”) was prepared in a steamjacketed tank with deionized water at 85° C. 220 kilograms of mannitolpowder and 30 kilograms of sorbitol were dissolved in the hot water. Thefeed solids concentration was calculated to be between 45 and 46% usingan Infra Red Moisture Analyser. A 7″ CSE disc was used to atomize thefeed. The inlet temperature was varied between 190 and 210° C. duringthe trials and the outlet temperature was varied, by adjusting the feedrate, to between 90 and 92° C.

Feed batch 1 was made up using MANNOGEM-EZ™. The initial operatingparameters included a disc speed of 11,500 rpm, spray dryer outlettemperature of 89° C., and a fluid bed outlet temperature of 92° C. Theproduct moisture of sample 1 was 1.03% with a particle size of 35%greater than 125 microns.

In Sample 2, a slightly higher fluid bed outlet temperature of 96° C.was used. This produced a product having a moisture content of 0.98%,with a particle size of 80.39% greater than 125 microns.

Spray dryer operating parameters were adjusted to operate with a dryerinlet air temperature of 205° C. and a dryer outlet air temperature of92° C. for Sample 3. The fluid bed air temperature rose to 99° C. usingthese parameters. The product demonstrated a moisture content of 1.75%.The product particle size was assessed as 79.45% greater than 125microns.

Sample 4 was assessed using alternative parameters. The spray dryerinlet temperature was adjusted to 210° C., with an outlet temperature of95° C., and a fluid bed air temperature of 94° C. Sample 4 had amoisture of 1.35%, and a total of 81.98% of particles above 125 microns.

Finally, the dryer was adjusted to give an inlet air temperature of 190°C., outlet air temperature of 90° C., and a fluid bed air temperature of94° C. Sample 5 showed a moisture level of 1.30%, with 52.31% ofparticles above 125 microns.

Five samples of Feed batch 2, prepared from C* MANNIDEX™ and SORBOGEM™were tested using the same drying conditions as above. Product moistureresults averaged 0.96%, and particle size averaged about 55.3% above 125microns.

Feed batch 3 was prepared from GETEC mannitol and SORBOGEM™. Trials werecarried out under the same set of plant operating parameters as thosefor batch one, and no adverse conditions were observed. The productsrecovered ranged in moisture content from 0.83% to 0.97%, with particlesizes between 48% and 61% greater than 125 microns.

Feed batch 4 was prepared from the same materials as Feed batch 1, andin addition, a method of dry mix addition into the fines recycle systemof the dryer was employed (“seeding”). This was achieved using avibratory feeder which was positioned at the inlet to the fines recyclefan. The dry feed used in the feeder was a dry blend of a 88:12 ratio ofGETEC mannitol to SORBOGEM™. The mannitol and sorbitol powders wereblended in a ribbon blender prior to loading the vibratory feeder. Thereason for the use of GETEC mannitol for the dry addition was due toinsufficient stock of MANNOGEM-EZ™ being available.

The main spray dryer feed was prepared using MANNOGEM-EZ™ and SORBOGEM™.The feed rate for the dry addition vibratory feeder was set at 50kilograms per hour in order to match the approximate wet feed rate ofthe spray dryer. Although each set of conditions was intended to becarried out in this experiment, only three of the four conditions weretested due to failure of the product discharge valve on the fluid bed.From the laboratory analysis of the samples produced, it would appearthat the addition of dry material into the fines recycle system resultsin the production of an overall drier product. Moistures in the productof 0.3-0.6% were recorded, and product particle sizes were slightlyfiner than those observed during the previous trials.

Dry solids addition into the fines recycle system appears to bebeneficial to achieving lower residual product moistures.

FIGS. 5A-5H illustrate the spherical nature of each of the spray-driedfinal products containing an 88:12 ratio of co-spray driedmannitol:sorbitol as demonstrated by scanning electron microscopy. FIG.5A is a SEM showing the co-processed particle resulting from use of theMANNOGEM-EZ™ in the co-spray drying process without seeding. FIG. 5B isa 100× magnification of FIG. 5A and shows a spherical structure having asomewhat filamentous structure on its surface. The moisture content forthis particle was determined to be 1.0%.

FIG. 5C is a SEM showing the co-processed particle resulting from use ofthe C* MANNIDEX™ in the co-spray drying process without seeding. FIG. 5Dis a 100× magnification of FIG. 5C and shows a spherical structurehaving a somewhat filamentous structure on its surface. The moisturecontent for this particle was determined to be 0.96%.

FIG. 5E is a SEM showing the co-processed particle resulting from use ofthe GETEC mannitol in the co-spray drying process without seeding. FIG.5F is a 100× magnification of FIG. 5E and shows a spherical structurehaving a somewhat filamentous structure on its surface. The moisturecontent for this particle was determined to be 0.82%.

FIG. 5G is a SEM showing the co-processed particle resulting from use ofthe MANNOGEM-EZ™ in the co-spray drying process with seeding. FIG. 5H isa 100× magnification of FIG. 5G and shows a spherical structure which isnon-filamentous on its surface. The moisture content for this particlewas determined to be 0.3%. It is thought that the addition of theseeding step significantly decreased the moisture content of theresulting co-processed particle. Further, with seeding, little or nofilamentous morphology is exhibited on the surface of the resultingparticle. As discussed above, lack of filamentous structure on thesurface of the resulting co-spray dried particle may lead to increasedflowability and enhanced quick-dissolve properties.

Table 3, below, illustrates representative values for the results of theexperiments detailed above.

TABLE 3 Batch No. 1 2 3 4 Sample No. 2  1  5  3  Disc Type (CSE) 7″ 7″7″ 7″ Disc Speed (RPM) 11500    11500    13000    13000    Inlet Temp.(° C.) 199   192   210   189   Outlet Temp. (° C.) 90   87   93   91  Fluid Bed Inlet 116   118   115   115   Temperature (° C.) Fluid BedOutlet 96   98   95   94   Temperature (° C.) Total Run Time (mins) 30  55   80   38   Prod. Weight (kg) 33.1 30   —  33.78 *Prod. Moisture (%) 0.98  0.96  0.83  0.33 +Particle Size Cum. >250μ  2.2  1.2  1.4  7.9(%) >200μ  9.6  4.9  2.6 15.9 (%) >125μ 80.4 49.2 47.9 44.9 (%) >100μ96.9 87.3 90.0 78.0 (%)  >90μ 99.6 98.7  98.21 91.0 (%)  <90μ 100  100   100   100   (%) *Product Moisture measured by Karl Fisher AF8.+Particle size measured with 200 mm sieves using the soft brush methodafter being on a sieve shaker.

Example 6 Differences in Morphology and Quick-Dissolve Aspects Based onFeed Rate of Dry Blend During Seeding

Experiments were performed as described above in Example 5 for “Batch4”. Various dry feed rates for seeding were tested to determine whetherthe dry feed rate had an impact on morphology of the resulting particle.Feed rates of about 12.5 kg/hr, 50 kg/hr, and 75 kg/hr were tested onplacebo formulations of co-spray dried 88:12 mannitol:sorbitol mixtures,which were seeded with a dry blend of an 88:12 mannitol:sorbitolmixture. A co-granulated blend of co-spray dried mannitol (MANNOGEM EZ™,SPI Pharma, Inc.) and crystalline sorbitol (SORBOGEM™, SPI Pharma, Inc.)in a ratio of 88:12 was run as a control.

FIG. 7 illustrates the results of a compactibility study on placebotablets prepared according to Example 5 and produced by co-spray dryingwith dry seeding using various dry-feed rates. Lower compression forcesproduce tablets with increased hardness, and the dry feed rate seemed tohave no effect on tablet hardness. Each feed rate produced a similar,steep curve. For example, a feed rate of 12.5 kg/hr at a compressionforce of 8 KN produced a tablet having a harness of about 8.0 KP. A feedrate of 50 kg/hr at the same compression force produced a tablet havinga hardness of about 8.5 KP. A feed rate of 75 kg/hr also produced atablet having a hardness of about 8 KP at the same compression force.Each of the formulations which were seeded with a dry blend produced atablet having at least a hardness of 11 KP before reaching a compressionforce of 10 KN. The control formulation produced a tablet having ahardness of about 4 KP at a compression force of 8 KN, and at 10 KNproduced a tablet having a hardness of about 6 KP.

FIG. 8 illustrates the results of an in-vivo disintegration time studyon tablets prepared according to Example 5 and produced by co-spraydrying with dry seeding using various dry-feed rates. Again, dry-feedrates seemed to have no effect on in vivo disintegration times. Astablet hardness increased, disintegration time increased slightly.However, even with a tablet hardness of around 11 KP, disintegrationtimes for each formulation were still less than 50 seconds. At alltablet hardness points, the control formulation without dry seedingdisintegrated in less time, however, these differences in disintegrationtime do not seem to be significant as indicated by the error bars.

Comparing FIG. 8 and FIG. 3, the in vivo disintegration times appear tobe slightly enhanced by the addition of the dry-blend during theco-spray drying process. In both Formulation A (90:10 mannitol:sorbitol)and Formulation D (80:20 mannitol:sorbitol) of FIG. 3 (no dry-blendaddition), the in vivo disintegration time exceed 50 seconds at a tablethardness of 8 KP, while in FIG. 8, the in vivo disintegration timesrange between 38 and 44 seconds at 8 KP for each of the formulationswith a dry-blend added at different dry feed rates.

FIGS. 9A-9C and 10A-10C are SEMs of the particles produced by seedingwith a dry-blend of mannitol:sorbitol in the same ratio used forco-spray drying. The dry feed rate used in the experiment which producedthe particles shown in FIGS. 9A-9C and 10A-10C were 12.5 kg/hr and 75kg/hr, respectively. There was no significant difference in themorphology of these particles. The particles continue to be sphericaland little or no filamentous structure is observed on the surface of theparticles.

It has been concluded that the dry-feed rate does not impact themorphology of the resulting particle; the quick dissolve aspects of thetablets produced from particles seeded with dry-blends ofmannitol:sorbitol have been enhanced by the addition of the dry-blend inthe co-spray drying process, as indicated by the decrease in in-vivodisintegration time.

Example 7 Dilution of the Co-Processed Product with MANNOGEM EZ™ andPOLYPLASDONE XL™

Formulations were prepared as in Experiment 6. Two additionalformulations were prepared as described in Experiment 6, using a dryfeed rate of about 37.5 kg/hr for “seeding.” These additionalformulations were diluted after the co-spray drying process with either20% or 40% of a mixture of about 90% MANNOGEM EZ™ and about 10%POLYPLASDONE-XL™ (“EZ/XL”). In-vivo disintegration time, compactibility,and friability were measured for each of the formulations.

FIG. 11 graphs the results for in vivo disintegration times for each ofthe 5 formulations tested. The control formulation is indicated by the“square” line marker. Even at the highest tablet hardness value of about11 KP, the disintegration time for any formulation did not exceed about46 seconds. The formulations diluted with the EZ/XL mixture seemed tohave slightly superior disintegration properties, as indicated in FIG.11. For example, at a tablet hardness of about 8 KP, the disintegrationtimes for both EZ/XL formulations were slightly lower (about 1 to 8seconds lower) than the formulations which were not diluted. Thevariation in disintegration times is more pronounced at lower tablethardness values. For example, at a tablet hardness of about 4 KP, theEZ/XL formulations disintegrated in about 26 to 28 seconds, while theother formulations took about 30 to 35 seconds to disintegrate. Thecontrol formulation disintegrated in about 24 seconds. Thus, it wasconcluded that the EZ/XL formulations increase the quick-dissolveproperties of the basic formulations.

FIG. 12 illustrates the compaction profile for each of the 5formulations and the control. Each of the seeded formulations had amaximum compression force of about 8.5 KN to about 10 KN, which produceda tablet having a hardness of about 10.8 KP to 11.5 KP. The EZ/XLformulations had a maximum compression force of about 10 KN to 12 KN,which produced a tablet having a hardness of about 10.3 KN to about 10.5KN. The control formulation displayed a maximum compression force ofabout 14 KN, which produced a tablet having a hardness of about 10 KN.Thus, it was concluded that the dilution process formed a tablet withsuperior compaction properties as compared with the control tablet.

FIG. 13 illustrates the percent friability for each of the 5formulations and the control. The percent friability for all of theformulations approached zero at a tablet hardness of about 6 KP. At atablet hardness of about 4 KP, all of the formulations had a percentfriability of about 0.5 to about 0.7, with the exception of the co-spraydried formulation seeded at a feed rate of about 50 kg/hr, which had apercent friability of about 0.25. It was concluded that the dilution ofthe co-spray dried formulations with the EZ/XL mixture had nosignificant effect on the friability of the tablet produced from thoseformulations. Thus, in vivo disintegration time can be decreased whilehaving no effect on friability.

The dilution process represents a viable alternative to simply co-spraydrying since it appeared to have little or no effect on friability, itdecreases in vivo disintegration time, and the compaction profile issuperior to the control profile.

Example 8 Quick Dissolve Preparations Comprising Spray-Dried Mannitol

A quick dissolving preparation according to the present invention, inthe form of tablets, was produced as set forth below.

A mixture of 2.0 kg of MANNOGEM™ EZ (SPI Pharma, New Castle, Del.), 0.23kg of silica gel (SYLOID®244FP, W.R. Grace & Co., Grace Davidson,Columbia, Md.) and 0.23 kg of colloidal silica (Cab-O-Sil M-5, obtainedfrom Cabot Corp., Tuscola, Ill.) was created by adding the components totwo polyethylene bags which were then shaken for about five (5) minutes.

The mixture was then discharged to a 10 cubic foot V-blender(Patterson-Kelly 10 cubic foot) along with the following additionalmaterials: 103.78 kg MANNOGEM EZ™ (added in two approximately equalparts), 5.63 kg of POLYPASDONE XL-10™ (ISP Technologies, 1361 Alps Road,Wayne, N.J. 07470), 3.75 kg of sodium croscarmellose (Ac-Di-Sol®, FMCBio polymer, Newark, Del.), and 9.38 kg of Starch 1500 (Colorcon, WestPoint, Pa.). The blender was than started and the contents of theblender were blended for 20 minutes at a moderate speed (about 6-20 RPM)to form an initial mixture.

After the blending step, the contents of the blender were dischargedinto containers.

In some instances, it may be necessary to de-lump the ingredients, forexample by passing the ingredients through a screening step (e.g., using20 or 30 mesh screens) before they are added to the blender. This isespecially true for the MANNOGEM EZ™, which should be checked for lumpsor large agglomerates before it is added to the blender.

A tableting mixture was prepared by adding 1024.5 grams of the initialmixture, 226.1 grams of acetaminophen (Eurand Acetaminophen microcaps,Vandalia, Ohio), 13 grams of peppermint flavor (FONA 894.022, CarolStream, Ill.), 6.5 grams of menthol flavor (FONA 875.008.5 Carol Stream,Ill.); 1.95 grams of aspartame (Aspartame, Nutrasweet, Augusta, Ga.) toa two liter glass vessel (Turbula T2C and blended for 15 minutes at 30rpm. After the 15 minute blending step, 13 grams of magnesium stearate(Mallinckrodt, St. Louis, Mo.) and 13 grams of talc (Talc 140 fromMutchler, Westwood, N.J.) are added to the blender and the blender isrestarted for 5 minutes at 30 rpm to form the final tableting mixture.

The final tableting mixture is transferred to the hopper of 16 stationtablet press with two punches fitted (Cadmach DC-60, Key Instruments,Englishtown, N.J.) and processed into 500 mg tablets using one-half inchflat beveled edge tooling (D-Tooling half inch flat beveled edge(bisect). The tablet press speed was 22 RPM resulting in 44 tablets perminute. The final tablets were cylindrical in shape and had thefollowing dimensions: 12.89 mm circular diameter and 3.85 mm thick. Eachtablet weighed about 500 mg and contained about 86.95 mg ofacetaminophen as the active ingredient. The hardness of the tablets wasabout 40N and the friability of the tablets (standard USP method) wasabout 8%. These tablets would need to be packaged in protective packages(e.g., blister packs) so that the friability would be less than 1% (inthe packaged form).

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of the present invention provided they comewithin the scope of the appended claims and their equivalents.

What is claimed is:
 1. A method for producing a directly compressibleand highly compactible composition, said method comprising: dissolvingmannitol powder and sorbitol powder into a solution; seeding thesolution with a blend of co-spray-dried particles consisting essentiallyof mannitol and sorbitol, wherein the ratio of mannitol powder tosorbitol powder in the solution is the same as the ratio of mannitol tosorbitol in the blend of dry particles; drying the solution in an airstream; and forming particles having a nonfilamentous microstructurefrom the solution.
 2. The method of claim 1, further comprising adding adisintegrant to the composition.
 3. The method of claim 2, wherein thedisintegrant is selected from the group consisting of crospovidone,croscarmellose, sodium starch glycolate, and combinations thereof. 4.The method of claim 2, further comprising adding a glidant to thecomposition.
 5. The method of claim 4, wherein the glidant is selectedfrom the group consisting of colloidal silica, silica gel, precipitatedsilica, and combinations thereof.
 6. The method of claim 1, furthercomprising adding an active ingredient.
 7. The method of claim 1,further comprising forming a tablet comprising the particles.
 8. Aquick-dissolving composition comprising: particles having a surface witha nonfilamentous microstructure, the particles comprising (i)co-spray-dried polyols consisting essentially of sorbitol and mannitol,wherein the particles are produced by seeding a solution comprising thepolyols selected in (i) with a blend of dry particles of the polyolsselected in (i), wherein the ratio of the polyols in the solution is thesame as the ratio of the polyols in the blend of dry particles; and adisintegrant, wherein said composition dissolves in the oral cavity inless than 60 seconds.
 9. The composition of claim 8, further comprisinga glidant.
 10. The composition of claim 8, wherein said disintegrant isselected from the group consisting of crospovidone, croscarmellose,sodium starch glycolate, and combinations thereof.
 11. The compositionof claim 9, wherein said glidant is selected from group consisting ofcolloidal silica, silica gel, precipitated silica, and combinationsthereof.
 12. The composition of claim 8, wherein said polyols comprisemannitol and sorbitol, wherein said mannitol is present in a range of 60to 99.5 percent and wherein said sorbitol is present in a range of 0.5to 40 percent.
 13. The composition of claim 12, wherein said mannitol ispresent in a range of 70 to 95 percent and wherein said sorbitol ispresent in a range of 5 to 30 percent.
 14. The composition of claim 13,wherein said mannitol is present in a range of 80 to 90 percent andwherein said sorbitol is present in a range of 10 to 20 percent.
 15. Thecomposition of claim 8, further comprising an active ingredient.
 16. Thecomposition of claim 15, wherein said active ingredient is coated. 17.The composition of claim 15, wherein said active ingredient is uncoated.18. The composition of claim 8, wherein said composition is directlycompressible.
 19. A tablet comprising the composition of claim
 8. 20. Acomposition comprising: (a) particles including co-spray dried mannitoland sorbitol, wherein the particles are produced by seeding a solutioncomprising mannitol and sorbitol with a blend of dry particlesconsisting essentially of mannitol and sorbitol, wherein the ratio ofthe mannitol to the sorbitol in the solution is the same as the ratio ofthe mannitol to the sorbitol in the blend of dry particles; wherein theparticles have a nonfilamentous microstructure; (b) a disintegrantselected from the group consisting of crospovidone, croscarmellose,sodium starch glycolate, and combinations thereof; (c) a glidantselected from the group consisting of silica gel, colloidal silica,precipitated silica, and combinations thereof; and (d) an activeingredient.